Discovery of the First Potent and Orally Available Agonist of the Orphan G‑Protein-Coupled Receptor 52

G-protein-coupled receptor 52 (GPR52) is an orphan Gs-coupled G-protein-coupled receptor. GPR52 inhibits dopamine D₂ receptor signaling and activates dopamine D₁/<i>N</i>-methyl-d-aspartate receptors via intracellular cAMP accumulation, and therefore, GPR52 agonists may have potential as a novel class of antipsychotics. A series of GPR52 agonists with a bicyclic core was designed to fix the conformation of the phenethyl ether moiety of compounds <b>2a</b> and <b>2b</b>. 3-[2-(3-Chloro-5-fluorobenzyl)-1-benzothiophen-7-yl]-<i>N</i>-(2-methoxyethyl)­benzamide <b>7m</b> showed potent activity (pEC₅₀ = 7.53 ± 0.08) and good pharmacokinetic properties. Compound <b>7m</b> significantly suppressed methamphetamine-induced hyperactivity in mice after oral administration of 3 mg/kg without disturbance of motor function

Discovery of [<i>cis</i>-3-({(5<i>R</i>)‑5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro‑1<i>H</i>‑inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5<i>H</i>)‑yl}carbonyl)­cyclobutyl]­acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist

A series of tetrahydro­naphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydro­isoquinoline compound <b>1</b> by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound <b>7</b> with a lower log <i>D</i> value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [<i>cis</i>-3-({(5<i>R</i>)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1<i>H</i>-inden-5-yl)­carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6­(5<i>H</i>)-yl}­carbonyl)­cyclobutyl]­acetic acid, TAK-828F (<b>10</b>), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound <b>10</b> exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound <b>10</b> was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases

Discovery of [<i>cis</i>-3-({(5<i>R</i>)‑5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro‑1<i>H</i>‑inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5<i>H</i>)‑yl}carbonyl)­cyclobutyl]­acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist

A series of tetrahydro­naphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydro­isoquinoline compound <b>1</b> by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound <b>7</b> with a lower log <i>D</i> value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [<i>cis</i>-3-({(5<i>R</i>)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1<i>H</i>-inden-5-yl)­carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6­(5<i>H</i>)-yl}­carbonyl)­cyclobutyl]­acetic acid, TAK-828F (<b>10</b>), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound <b>10</b> exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound <b>10</b> was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases